Project Summary/Abstract: Therapy-induced peripheral neuropathy (TIPN) is a very common and often dose-limiting side effect of anti-cancer therapy. Clinically, TIPN is a predominantly sensory peripheral neuropathy characterized by numbness, tingling, and often, neuropathic pain. These symptoms can persist for years after cessation of treatment, and so TIPN can significantly diminish patient's quality-of-life both during and after treatment. Moreover, the development of TIPN often necessitates reducing drug dosage or switching regimens, and therefore limits the effectiveness of anti-cancer therapy. Currently, there are no effective treatments for TIPN. Axon loss is a hallmark of this neuropathy, suggesting that mechanistically distinct chemotherapeutics may feed into a common axonal degeneration program. We have demonstrated that genetic inhibition of SARM1, the central executioner of this core axonal degeneration program, blocks the development of TIPN in a mouse model of vincristine-induced peripheral neuropathy. The SARM1 pathway induces axon loss by triggering depletion of the essential metabolic co-factor NAD. Here we seek to block the development of TIPN by countering this loss of NAD in order to maintain axonal health. We also explore mechanisms to block the activation of SARM1 as novel therapeutic strategies for blocking the development of TIPN. Finally, targeting the SARM1 pathway will be a useful treatment for TIPN if manipulating this pathway does not affect tumor growth or chemotherapeutic efficacy. We will explore this using genetic tumor models. If successful, this project will identify novel treatment strategies for the prevention of TIPN.